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Desensitising Celiac Disease Patients With the Human Hookworm (NaCeD)

This study has been completed.
Sponsor:
Collaborator:
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Dr John Croese, The Prince Charles Hospital
ClinicalTrials.gov Identifier:
NCT01661933
First received: August 6, 2012
Last updated: October 10, 2014
Last verified: October 2014
August 6, 2012
October 10, 2014
August 2012
March 2014   (Final data collection date for primary outcome measure)
Duodenal Villus Height:Crypt Depth [ Time Frame: Week -24 to -36 ]
Biopsies were fixed in neutral buffered formalin, processed and carefully orientated and embedded in paraffin wax. Sections (3 µm) were stained with H&E. Slides from both time-points were de-identified, shuffled and graded by Dr John Croese after which results from poorly orientated slides were verified by Dr Andrew Clouston. The Vh:Cd ratios were measured on 5 randomly selected well-orientated sites. The null hypothesis is that hookworm infection will not protect against mucosal damage following 12-week exposure to gluten in celiac disease.
Duodenal Villus Height:Crypt Depth [ Time Frame: up to 36 weeks ]
Biopsies will be fixed in neutral buffered formalin, processed and carefully orientated and embedded in paraffin wax. Sections (3 µm) will be stained with H&E and immunostained with anti-CD3 and -CD8 (lymphocyte) and anti-CD94 (NK cell). All slides will be blinded and scores will be graded by Dr John Croese after which randomly selected counts will be verified by Dr Andrew Clouston. The Marsh score will be scored as Marsh 3A = 1, 3B = 2 and 3C = 3. CD3+IEL per 100 intestinal epithelial cells (IEC) will be counted at 24 randomly selected sites between the villus tip to the base of the crypt in each biopsy to establish a IEL:IEC ratio. The Vh:Cd ratios will be measured independently of the Marsh grading, to be performed on 10 randomly selected well-orientated sites. The null hypothesis is that hookworm infection will not protect against mucosal damage following 12-week exposure to gluten in celiac disease.
Complete list of historical versions of study NCT01661933 on ClinicalTrials.gov Archive Site
  • Intraepithelial Lymphocyte Count [ Time Frame: Week-24 and -36 ]
    Biopsies were fixed in neutral buffered formalin, processed and carefully orientated and embedded in paraffin wax. Sections (3 µm) were stained with anti-CD3. All slides were de-identified and graded by Dr John Croese. The IEL percentages were measured on 2 or more randomly selected well-orientated villi. The null hypothesis is that hookworm infection will not protect against mucosal IEL influx following 12-week exposure to gluten in celiac disease.
  • Number of Participants With 2 Points Increase in Marsh Score Post GC-1g [ Time Frame: Longitudinal change between week-24 and week-36 ]
    The Marsh score is a defined but qualitative assessment assigned a value to allow for comparison. The scores were evaluated by consensus between the primary (chief) investigator and the study pathologist. The Marsh score was graded 0, 1, 2, 3A (assigned-4), 3B (-5) and 3C (-6); rage 1-6 with normal=0 and severe inflammation=6. Because the scoring is vulnerable to artefact, only a 2-point shift was regarded as a significant intra-individual change. The scores were graded after week-36 on biopsies de-identified shuffled. An upward shift was interpreted to reflect a significant worsening of gluten-associated inflammation. The comparison reported evaluated changes from baseline (week-24) to post-low-dose gluten challenge (week-24; GC-1g). The objective for using the Marsh score was to identify individuals who might have experienced a severe worsening in pathology due to GC-1g that might not be reflected in the Vh:Cd group analysis.
  • Serum Anti-tissue Transglutaminase Antibodies Measured as International Units/mL (IU/mL) [ Time Frame: Anti-tTG IU/mL levels pre-trial, mid-trial and after 3 gram/day gluten challenge ]
    The trial was extended with pre-trial and mid-trial anti-tTG antibody levels used to compare with the post-trial levels. Anti-tTG is a serological measure of tissue transglutaminase-2 antibodies. In active celiac disease, levels are increased. In treated disease, levels are low (normal cut-off was <15 IU/mL). A significant increase compared to baseline in tTG can be expected 2 weeks after consuming 3g of gluten daily for 2 weeks in people with celiac disease who have been maintaining a gluten-free diet, but who are not taking other treatment.
  • Intraepithelial Lymphocyte Count [ Time Frame: Week-24 and -36 ]
    See above
  • Marsh Score [ Time Frame: Week-24 and -36 ]
    As above
Not Provided
Not Provided
 
Desensitising Celiac Disease Patients With the Human Hookworm
Combining Necator Americanus With Trace Gluten to Restore Tolerance in Coeliac Disease: a Pilot Clinical and a Detailed in Vitro Immunological Study.
We have established that the hookworm Necator americanus (Na) dramatically alters the local and systemic immune landscape of the infected human host. Consistent with the principle of desensitisation, diet managed celiac disease subjects previously infected by us with Na will be invited to receive small incremental doses of gluten as pasta (3-25 mm straw of spaghetti) over 16 weeks. Each participant will then be carefully re-assessed to determine if it is appropriate to undertake a 12-week gluten challenge.

Hypothesis The adaptive Th2/regulatory profile imposed by Na will promote gluten tolerance following a micro-dose desensitising programme.

Primary Aim: To determine the safety and efficacy of Na as a tolerising agent in celiac subjects

Specific Aim 1. Undertake a therapeutic pilot study comparing mucosal histopathology before and after a gluten challenge, to be preceded by a programmed desensitising micro-challenge using Na as a tolerising agent.

Specific Aim 2. Assess systemic and mucosal immune responses to gluten micro-challenge, Na infection, and gluten re-challenge throughout the pilot study, to be referenced against hookworm-naive people with treated and untreated celiac disease.

Specific Aim 3. Utilising blood and tissue from hookworm-naive celiac disease volunteers, undertake in vitro studies focusing on the effects of Na-derived excretory/secretory (ES) products on gluten-stimulated gut mucosal cell apoptosis, cytokine and gene profiles.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Celiac Disease
  • Biological: Necator americanus
    Previously inoculated subjects will be further inoculated as previously undertaken with 20 3rd stage infective Na larvae (10 + 10 over 4 weeks). Four weeks after the 2nd inoculation, each participant will receive a micro-dose of gluten (10 mg daily) as pasta for 8 weeks, to be followed by a low-dose of gluten (50 mg daily) for 8 weeks. After this, a detailed assessment involving upper endoscopy and duodenal biopsy will be performed before deciding on an individual case basis that it is safe for the participant to proceed to challenge. A gluten challenge of 1 G (15-20 G of pasta or a ½ slice of standard white bread) twice weekly for 12 weeks will commence.
    Other Name: Hookworm
  • Biological: Necator americanus
    After completion of the previously planned challenge, volunteers will be invited to extend the gluten challenge. The extension is for 4 weeks total. The gluten challenge is stepwise: gluten 10 mg daily for one week, 50 mg daily for one week and finally 3 grams daily for 2 weeks. The outcome measure is serum tissue transglutaminase to be compared before and after the intervention.
    Other Name: Hookworm
Experimental: Necator americanus, gluten challenge
Single arm, vertical.
Interventions:
  • Biological: Necator americanus
  • Biological: Necator americanus
Daveson AJ, Jones DM, Gaze S, McSorley H, Clouston A, Pascoe A, Cooke S, Speare R, Macdonald GA, Anderson R, McCarthy JS, Loukas A, Croese J. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011 Mar 8;6(3):e17366. doi: 10.1371/journal.pone.0017366.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
12
March 2014
March 2014   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Previously enrolled adults who received an experimental hookworm infection with diet treated celiac disease.

Exclusion Criteria:

  • Immune suppressive therapies
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Australia
 
 
NCT01661933
AU/3/BOBD012
Yes
Not Provided
Not Provided
Dr John Croese, The Prince Charles Hospital
The Prince Charles Hospital
National Health and Medical Research Council, Australia
Study Director: John Croese, MD The Prince Charles Hospital, Centre for Biodiscovery and Molecular Development of Therapeutics
Principal Investigator: Dianne Jones, BAppSc Logan Hospital
Principal Investigator: Alexander Loukas, PhD Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University
The Prince Charles Hospital
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP